Antibiotic or silver versus standard ventriculoperitoneal shunts (BASICS): a multi-centre,

single-blinded, randomised trial and economic evaluation

* Professor Conor L Mallucci1 FRCS

*Michael D Jenkinson2,3 FRCS

Elizabeth J Conroy4 MSc

John C Hartley5 FRCPath

Michaela Brown4 MSc

Joanne Dalton4 BA

Tom Kearns4

Tracy Moitt4

Michael J Griffiths6, 7 FRCP

Giovanna Culeddu8 MSc

Professor Tom Solomon6, 9 FRCP

Professor Dyfrig Hughes8 PhD

Professor Carrol Gamble4 PhD

For the BASICS study Collaborators

*Joint 1st authors

1Department of Paediatric Neurosurgery

Alder Hey Children’s Hospital

Liverpool, UK

1

2Department of Neurosurgery

The Walton Centre NHS Foundation Trust

Liverpool, UK

3Institute of Translational Medicine

University of Liverpool

Liverpool, UK

4Clinical Trials Research Centre

University of Liverpool

Liverpool, UK

5Department of Microbiology

Great Ormond Street Children’s Hospital

London, UK

6Institute of Infection and Global Health

University of Liverpool

Liverpool, UK

7Department of Paediatric Neurology

Alder Hey Children’s Hospital

Liverpool, UK

2

8Centre for Health Economics and Medicines Evaluation

Bangor University

Bangor, UK

9 Department of Neurology

The Walton Centre NHS Foundation Trust

Liverpool, UK

Correspondence to:

Professor Conor L Mallucci

Department of Paediatric Neurosurgery

Alder Hey Children’s Hospital

Liverpool, L12 2AP, UK

cmallucci@me.com

Tel: 07710 498920

Word counts

Abstract: 294

Main text: 4459

Tables: 3

Figures: 2

3

Summary

Background

Insertion of a ventriculoperitoneal shunt for hydrocephalus is one of the commonest

neurosurgical procedures worldwide. Shunt infection affects up to 15% of patients, resulting

in long hospital admission, multiple surgeries, reduced cognition and quality of life. The aim

of this trial was to determine the clinical and cost-effectiveness of antibiotic (rifampicin and

clindamycin) or silver shunts compared to standard shunts at reducing infection.

Methods

Patients with hydrocephalus of any aetiology, undergoing insertion of their first

ventriculoperitoneal shunt were randomised (1:1:1) to receive standard, antibiotic or silver

shunts. Twenty-one neurosurgery units in the UK and Ireland participated. Participants

receiving a shunt without evidence of infection at the time of insertion were followed for a

maximum of two years. The primary outcome was time to shunt failure due the infection

analyzed using Fine and Gray survival regression models for competing risk . Outcomes were

analyzed by intention-to-treat. . [ISRCTN49474281].

Findings

Between June 26, 2013 and Oct 9, 2017, 1605 patients, from neonate to 91 years of age,

were randomised to 536 standard, 538 antibiotic, and 531 silver shunts. 1594 had a shunt

inserted without evidence of infection at time of insertion and were followed up for a

median of 22 months (IQR [10-24]; completeness 98.4%). 32 (6%) of 533 patients

randomised to standard shunts had a shunt revision for infection, compared to 12 (2.2%) of

535 randomised to antibiotic shunts (cause specific Hazard Ratio (csHR) [97.5% confidence

interval]: 0·38, [0·18, 0·80], p<0·01) and 31 (5.9%) randomised to silver shunts (csHR: 0·99,

[0·56, 1·74], p<0·96). Antibiotic shunts save £135,753 per infection avoided.

4

Interpretation

The BASICS trial has provided definitive evidence to support the adoption of antibiotic

shunts in all patients having their first ventriculoperitoneal shunt in the UK.

Funding

This study was funded by the National Institute for Health Research Health Technology

Assessment programme under grant agreement 10/104/30.

Disclaimer

The views expressed are those of the authors and not necessarily those of the NHS, the NIHR

or the Department of Health and Social Care.

Key words

Ventriculoperitoneal shunt, infection, clinical trial, antibiotic, silver, standard

5

Introduction

Hydrocephalus affects one in every five hundred births.1 It also affects older children and

adults of all ages and can be secondary to a variety of causes including haemorrhage,

trauma, infection and intracranial tumours.2 A recent systematic review and meta-analysis

reported the hydrocephalus prevalence to be 88/100,000 in children, 11/100,000 in adults

and 175/100,000 in the elderly.3 The commonest treatment for hydrocephalus is the

ventriculoperitoneal shunt, which comprises proximal (ventricular) and distal (peritoneal)

silicone catheters joined by a valve to drain cerebrospinal fluid (CSF) from the ventricles into

the peritoneal cavity. Insertion of a ventriculoperitoneal shunt for hydrocephalus is one of

the commonest neurosurgical procedures worldwide.4 Failure of this shunt due to infection

occurs in 7-15% of patients.5,6 Episodes of infection have a major impact on patients, require

prolonged hospitalization and antibiotics, surgery to remove the infected shunt and to place

a new shunt once the infection has been treated. Shunt infection impacts on health-related

quality of life, cognitive function,7 and survival, with the number of infections being an

independent predictor of death.8

Impregnated shunt catheters have been introduced as a means to reduce infection in

addition to the usual surgical site infection prevention care bundles. There are three types of

shunt catheter: standard, antibiotic impregnated (0.15% clindamycin and 0.054% rifampicin)

and silver impregnated. Systematic reviews and meta-analyses did not find any high quality

evidence to support their comparative effectiveness at reducing shunt infection9,10.

Consequently, practice is variable across the world, with selection based on neurosurgeon

preference and costs.

We conducted the British Antibiotic and Silver Impregnated Catheters for

ventriculoperitoneal shunts multi-center randomised controlled trial (BASICS) to assess the

6

clinical and cost-effectiveness of antibiotic and silver shunts at reducing shunt failure due to

infection, compared to standard shunts in patients undergoing insertion of their first

ventriculoperitoneal shunt for hydrocephalus.

Methods

Study design

In this parallel, multi-centre randomised controlled trial we compared standard, antibiotic

and silver shunts in patients undergoing insertion of their first ventriculoperitoneal shunt for

hydrocephalus. Trial sites were twenty-one regional adult and paediatric neurosurgery

centers in the United Kingdom and Republic of Ireland (See Section 1 of the Supplementary

Appendix). Ethics approval was obtained from the North West Greater Manchester research

ethics committee (ref: 12/NW/0790). The trial protocol (available at

www.journalslibrary.nihr.ac.uk/programmes/hta/1010430/#/) has been published

previously11 (Substantial amendments are detailed in Section 6 of the Supplementary

Appendix).

Participants

To undergo randomisation in the trial, patients could be any age, and have hydrocephalus of

any aetiology requiring a first ventriculoperitoneal shunt. Patients with failed primary

endoscopic third ventriculostomy, previous indwelling external ventricular drain and

indwelling ventricular access device were included. Patients were excluded if they had

evidence of active and on going CSF or peritoneal infection, a previous indwelling

ventriculoperitoneal shunt, multi-loculated hydrocephalus requiring multiple shunts or

neuro-endoscopy, known allergy to rifampicin, clindamycin or silver, or if a ventriculo-atrial

or ventriculo-pleural shunt was planned. Patients gave written informed consent or assent

7

for minors as appropriate. Consent for adults lacking capacity was obtained from a

consultee, usually the next of kin, or an independent healthcare professional, and it was

later sought again from the participant once capacity was regained.

Randomisation

Patients were randomised to standard, antibiotic or silver shunts at a ratio of 1:1:1 in

random permuted blocks of 3 and 6. The randomisation sequence was generated by an

independent statistician, and stratified by neurosurgical unit and age group (adult or

paediatric, defined according to unit practice). The randomisation was revealed in the

operating theatre at the time the shunt was required using opaque tamper-proof sealed

envelopes that were opened by tearing perforated edges. Due to the different colour of the

shunts it was not possible to blind the neurosurgeon and operating staff. Shunt type was not

recorded in the operating record and was not disclosed outside the operating room. Training

on non-disclosure of shunt type was provided to all investigators. All shunt types were used

in accordance with the manufacturer’s instructions for their intended purpose. Patients

were blind to the type of shunt inserted.

Procedures

Data were collected at baseline; randomisation (pre-operative assessment);

randomisation (first surgery); early post-operative assessment; first routine post

operative assessment; 12 weekly follow up assessments; subsequent routine post

operative assessments; and, where applicable, unscheduled visits/admissions and at

shunt revision/removals (see section 2 of supplementary material). All patients received

prophylactic antibiotics at the time of shunt insertion as per standard neurosurgical

practice. All other parameters related to surgical shunt insertion technique e.g. choice of

skin preparation, hair shave or not, number and seniority of neurosurgeon, position on

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operating list were recorded but not standardised and were undertaken according to

each participating neurosurgery unit’s practice. Patients were followed for a minimum 6

months and maximum 2 years.

Outcomes

The primary outcome was time to shunt failure due to infection as assessed by a blinded

central review panel comprised of the Chief Investigator [CLM] (or delegate for participants

treated by the chief investigator [MDJ]) and trial microbiologist [JCH], masked to allocations.

At first shunt revision, sites recorded data on clinical presentation (e.g. temperature,

headache, lethargy, meningism, conscious level, wound erythema), peripheral white blood

cell count, C-reactive protein (CRP), microbiology analysis of CSF (microscopy and culture),

and treatment initiated (e.g. antibiotics prescribed, shunt removed). Based on these

parameters the shunt failure was classified as being due to infection or not. Shunt infections

were further defined as: (1) Definite – culture positive: growth of organisms from CSF on

primary culture or repeated (>1) subculture [the passage [growth identified following

enrichment of cells from the primary culture to fresh medium by overnight broth

incubation], with or without clinical signs of infection, and managed by shunt removal and

antibiotic treatment; (2) Probable – culture uncertain: growth of organisms from CSF on one

subculture only, with or without clinical signs of infection, with CSF pleocytosis and/or

organisms on gram stain, and managed by shunt removal and antibiotic treatment; (3)

Probable – culture negative: no organisms growth but, with or without clinical signs of

infection, with CSF pleocytosis and/or organisms on gram stain, and managed by shunt

removal and antibiotic treatment; (4) Possible – culture uncertain: no signs of infection, no

CSF pleocytosis, no organisms seen on gram stain, growth after enrichment in one CSF

sample only, and managed by shunt removal and antibiotic treatment; and (5) Shunt deep

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incision infection: infection of the deep surgical wound and subcutaneous shunt without any

evidence of CSF infection.

Secondary outcomes were: time to removal of the first shunt due to suspected infection, as

defined by the treating neurosurgeon at the time of first revision; time to shunt failure of

any cause; reason for shunt failure (infection, mechanical [blockage of any component i.e.

valve or catheters], patient [unrelated medical condition e.g. appendicitis], functional

[change of valve for symptomatic over- or under-drainage of CSF e.g. fixed pressure to

programmable valve] as classified by treating neurosurgeon); types of bacterial shunt

infection [see table 2]; time to shunt infection following first clean revision as classified by

central review; Quality of life measured using the Hydrocephalus Outcome Questionnaire12

and health economic outcomes: incremental cost per shunt failure (any cause) averted and

per quality-adjusted life (QALY) gained using the EQ-5D-3L, EQ-5D-3L (proxy) or EQ-5D-3L-Y.

Data on complications and serious adverse events were collected (see protocol:

www.journalslibrary.nihr.ac.uk/programmes/hta/1010430/#/).

Statistical analysis

A Trial Steering Committee, comprising a majority of independent members viewing reports

blinded to treatment arm, and an Independent Data Monitoring Committee viewing

unblinded reports reviewed the trial regularly to assess conduct, progress including rates of

shunt infection, and safety. The sample size for the primary outcome used the method

described by Pintilie13 with the following assumptions: (i) failure for infection was the event

of interest with all other reasons for failure a competing risk; (ii) the rate of infection was 8%

in the standard shunt arm5 and 4% in the impregnated shunt (antibiotic or silver) arms; (iii)

the competing risk event rate was 30%; and (iv) 5% loss to follow-up. Based on this a total

sample size of 1200 with 119 events demonstrated good statistical power (88%) with

10

leverage for a lower event rate. An interim analysis was planned after 50% of the total

events had been observed using Haybittle-Peto.14 Monitoring of the infection rates

demonstrated the majority of events occur within one month of shunt insertion (i.e. was not

exponentially distributed), and that the rates of infection, competing risk, and loss to follow

up were lower than expected. The independent data monitoring committee reviewed the

sample size calculations and recommended increasing recruitment to a target of 1606 with

101 events to provide 80% power; the trial steering committee agreed. The early occurrence

of events and assumption of exponential risk were managed in the Pintilie 13 assumptions by

reducing the accrual and follow up rates to one month. The analysis was conducted

according to a pre-specified statistical analysis plan, which was updated following review of

data by a statistician blind to comparative interim reports. Outcomes were analyzed

according to the intention-to-treat principle and safety analyses according to the type of

shunt in situ. To adjust for the three treatment arms, a p-value of 0·025 was considered

statistically significant and 97.5% confident intervals (CI) were used throughout. Outcome,

with shunt failure due to infection as the event of interest, used Fine and Gray15 survival

regression models with cause specific hazard ratios (csHR) and subdistribution hazard ratio

(sHR) presented.16,17 Cox regression models were used to analyse time to shunt failure of

any cause. The assumption of proportionality for time to event outcomes was checked

using Schoenfeld residuals. Reason for shunt failure is presented descriptively and with a

chi-squared test. Types of organisms cultured from CSF are presented descriptively. Quality

of life outcomes were analysed using mixed models for repeated measures. All survival

models were adjusted for the age category of the recruiting site (paediatric or adult), with

adult sites further categorised by age over 65 years. Age was used in preference to and

recruiting centre due to prognostic value of age group and the dependency between age

group and centre prevented inclusion of both covariates. Primary outcome and safety

analyses were validated by independent programming from the point of raw data extraction.

11

All analyses were done with SAS software version 9.4 with SAS/STAT package 14.3. The trial

was registered with ISCTRN: 49474281.

Economic analysis

The economic analysis (section 5 of the Supplementary Appendix) adopted the perspective

of the National Health Service in the UK to estimate the incremental cost per first shunt

failure (due to any cause) averted for antibiotic, silver and standard shunts. Within-trial

healthcare resource use was based on responses to questionnaires, routine hospital data via

Patient Level Information and Costing Systems, and entries in case report forms. Unit costs

for 2016-17 were taken from standard sources (Tables S12-S14).18-21 Silver cost £361·62,

antibiotic cost £384, and standard cost £172. In the base-case analysis, costs and outcomes

incurred in the second year were discounted at a rate of 3·5%, and any missing data were

multiply imputed using the method of chained equations. Total costs were analysed using

linear regression with the stratifying variables, time in study, intervention group, site and

treatment failure, as predictors. Mean outcome by intervention group was analysed in the

same way, but with total cost substituting treatment failure. Sensitivity analyses considered

(i) applying different discount rates (0%, 1·5% and 6% per annum for both costs and

outcomes); (ii) using observed data for costs (no multiple imputation); and (iii) using a

generalised linear model for analysing costs. Alternative forms of cost-effectiveness, and a

cost-utility analysis relating to participants aged ≥5 years were also conducted. A stratified

analysis was undertaken to estimate cost-effectiveness by age group - paediatrics, adults up

to 65, and ≥65 years of age.

Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data

interpretation, or writing of the report. The corresponding authors had full access to all the

12

data in the study and had final responsibility for the decision to submit for publication.

Results

Between June 26, 2013 and Oct 9, 2017, there were 1606 randomisations. One patient

was erroneously randomised twice and so data from the first randomization only were

used (Figure 1). Fifty-three participants subsequently withdrew from follow-up (see

Figure 1), of which 24 continued to provide routinely collected data. The characteristics

of the three groups were similar at baseline (Table 1, Tables S4 and S5).

1601 patients had a shunt inserted (99.8%) and 1585 received the allocated shunt

(Figure 1) 98·8%, N=1605). Patients not receiving a shunt (n=4), or with an infection at

insertion (n=7) were not included in the primary analysis set (Figure 1). The median

follow-up time for patients assessed for primary outcome was 22 months (LQ - UQ; 10-

24; min to max 0 to 24, N=1594).

398 patients had revision operations (25·0%, N=1594), with 75 being centrally classified

as shunt infections (4·7%, Table 2). When compared to the standard shunt over time, the

antibiotic shunt decreased the rate of shunt failure due to infection (csHR: 0·38, 97·5% CI:

[0·18, 0·80], p<·01; Table 3). Silver was comparable to standard shunts (csHR: 0·99, 97·5% CI:

[0·56, 1·74], p=0.96; Table 3). Figure 2 shows the cumulative incidence of failure due to

infection by shunt group. The majority of centrally assessed infections were classified as

definite – culture positive (53/75, 70·7%).

Of the total 398 revisions, 78 (4·9%, Table 2) were defined by the treating neurosurgeon as

due to suspected infection. Antibiotic but not silver shunts were associated with a significant

decrease of failure due to infection when compared to standard shunts (Table 3). The reason

for revision was classified by central review (primary outcome) and treating neurosurgeon

13

(secondary outcome) as infection or no infection, and this classification was the same in

95·7% (381/398) of revisions (Table S6).

Kaplan-Meier curves for time to shunt failure for any cause showed no significant difference

between antibiotic or silver in comparison to standard shunts (Table 3, Figure S2). The

number of shunt failures was similar between the three groups (Table 2), however the

underlying reason differed when comparing standard to antibiotic shunts (p=0·02, Table S7)

with fewer infections for antibiotic shunts but a higher frequency of failure due to other

causes.

Staphylococcus aureus (30%) and coagulase negative staphylococci (37·5%) accounted for

the majority of cultured organisms (Table S8). Culture results show a reduction in

staphylococcal/gram positive infections for antibiotic shunts compared to standard and

silver. All three shunt types had a similar number of gram-negative infections. The

proportion of culture positive infections was lowest in antibiotic shunts (50%), (compared to

68·8% in standard and 80·6% in silver shunts). The remaining infections were classified as

infection by the central review panel based on the CSF white cell counts, clinical features

and blood parameters (Table 2).

Following first clean (non-infected) revision (n=323), the proportion of patients with

revisions for any reason (infection and no infection) increased to 39·6% (128/323; Table S9).

This rate was 25% (398/1594) in de novo shunts (Table 2). The overall infection rate was also

higher within this subgroup compared to de novo shunts 6·2% (20/323, Table S9) versus

4·7% (75/1594, Table 2). There was no significant difference in time to infection following

first clean revision when comparing either antibiotic or silver (Table 3) to standard shunts.

14

The proportion of revisions of first shunt for any cause (paediatric: 225/592, 38·0%; adults

up to 65 years: 118/499, 23·6%; 65 years and over: 55/503, 10·9%, Table S10) and for

infection (paediatric: 47/592, 7·9%; adults up to 65 years: 23/499, 4·6%; 65 years and over:

5/503, 1·0%, Table S10) varied by participant age group. Compared to children, over time

adults up to 65 years, and adults 65 or over had a significantly lower rate of shunt failure due

to infection (adults under 65 csHR: 0·55, 97·5% CI: [0·31, 0·97], p=0·02; adults 65 or over

csHR: 0·12, 97·5% CI: [0·04, 0·34], p<0·01; Table 3). Figures S3 and S4 display the cumulative

incidence of time to shunt failure due to infection by age group and shunt stratified by age

group respectively. Schoenfeld residuals supported the assumption of proportionality used

in models of for time to event outcomes.

The level of missing cost data was balanced across the three intervention groups (Table

S15). Disaggregated resource use and costs are presented in Tables S16-S17. Mean total

costs were £18,707 (97·5% CI: £13,888, £26,966) for standard shunts, £14,192 (97·5%

CI: £12,450, £17,786) for antibiotic, and £17,385 (97·5% CI: £14,649, £22,355) for silver

shunts (Table S18). Responses to EQ-5D are presented in Tables S19-S21. In the base-

case analysis, the total costs relating to both silver and antibiotic shunts were less than

standard. Incrementally, silver shunts saved £62,358 for each additional first shunt

failure due to any reason compared with standard; and antibiotic shunts saved £638,600

per additional failure in comparison to silver (Table S22). In sensitivity analyses, the

incremental cost-effectiveness ratios were stable to changes in discount rate and choice

of regression modelling but, based on observed data, antibiotic dominated silver shunts,

and saved £56,771 for each additional failure compared with standard shunts. Antibiotic

shunts were most cost-effective in paediatrics, with mean savings of £5,312 and 0·004

fewer shunt failures (Table S23). A cost-effectiveness analysis based on the incremental

cost per infection averted indicated that silver shunts were dominated by standard,

15

whereas antibiotic shunts were dominant, saving £4,059 per 0·030 fewer infection-

related shunt failures (Table S24). There were insufficient data to formally analyse

Hydrocephalus Outcome Questionnaires and results are therefore presented descriptively

(Tables S25-S26). In the cost utility analysis, antibiotic shunts were dominated by silver.

Compared with standard, silver shunts were £183 more costly, and yielded 0 ·096

additional QALYs overall, resulting in an incremental cost-effectiveness ratio of £1,904

per QALY gained, and a probability of 0.52 of being cost-effective at a willingness to pay

of £20,000 per QALY (Figure S5).

There were no serious adverse events. A total 654 adverse events were reported in 413

patients (25·8%, N=1601 who received a shunt). The proportion of patients experiencing an

event was highest for silver shunts (Standard: 25·4%; Antibiotic: 23·3%; Silver: 36·4%, Table

S11). Common adverse events were ventricular catheter obstruction (96 events in 79

patients); shunt valve obstruction (65 events in 52 patients); and valve change for

symptomatic over drainage (54 events in 50). All of these were expected events in the

context of re-admission for shunt revision.

Discussion

In this trial of patients with hydrocephalus undergoing insertion of a first permanent

ventriculoperitoneal shunt the infection rates were 6·0% for those receiving standard

shunts, 2·2% for antibiotic shunts and 5·9% for silver shunts. Compared to standard shunts,

antibiotic shunts were significantly associated with a lower rate of infection while no such

effect was evident for silver shunts. This effect was present across all age categories. The risk

of shunt infection was highest in children, reducing in adults and being particularly low in the

elderly. There are significant economic benefits for every shunt infection averted, although

cost-effectiveness is greatest among those at highest risk.

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The BASICS trial provides definitive evidence in the debate on use of using antibiotic or silver

shunts to reduce infection. A previous randomised trial that was underpowered compared

antibiotic to standard shunts, but did not show a statistically significant difference in the risk

of infection (relative risk: 0·38 CI: 0·11, 1·30; p=0·12).22 Additionally, systematic reviews and

meta-analyses did not find any high quality evidence to support the comparative

effectiveness of antibiotic shunts at reducing infection.9,10 Silver catheters have only been

evaluated for use in temporary external ventricular drains, not permanent implanted shunts.

A randomised trial of external ventricular drains (silver versus standard) reported a

reduction in infection from 21·4% (30/140) to 12·3% (17/138) (p=0·042),23 although this is

much higher than the UK national reported infection rate (9·3%). 24 The BASICS trial was

therefore conceived to evaluate both antibiotic and silver shunts, which might otherwise

have been widely introduced into routine clinical practice despite a lack of firm evidence of

their efficacy. The results of our trial show that antibiotic shunts are both clinically and cost

effective and will inform neurosurgery practice and shunt choice for the benefit of patients.

Correctly diagnosing shunt infection when the CSF is culture positive is straightforward,

however this only applies to around 70% of cases. When the CSF is culture negative the

treating neurosurgeon must consider other parameters including, CSF white cell count,

clinical symptoms and signs and prior treatment with antibiotics. In these circumstances

removal of the shunt and antibiotic treatment often leads to resolution of the presumed

infection and patient recovery. The classification of shunt infection in our study was

determined by the central review committee (table 2), and the proportion of culture positive

infections was 68·8% in standard shunts, 50·0% in antibiotic shunts and 80·6% in silver

shunts. There was a lower rate of culture positive infection with antibiotic shunts. Our

analysis allowed for culture negative infections to be included when there was sufficient

17

supporting clinical evidence of shunt infection. This was because we postulated that the

presence of antibiotic and possibly silver shunts might reduce the ability to culture

organisms from infected shunts. Our study showed an even greater effect in favour of

antibiotic shunts when only culture positive infections were analysed. The reduction of

infections seen is consistent with the expected microbiological spectrum of the antibiotic

shunts, which are especially active against gram-positive organisms, and were designed to

prevent Staphylococcus species infection. The culture results show a large reduction in

staphylococcal infection compared to standard and silver shunts, which accounts for the

majority of the reduction. All three shunt types had a similar number of gram-negative

infections supporting the biological plausibility of our results.

It should be noted that the overall shunt failure rate was the same for all groups even

though infection was reduced in antibiotic shunts. When one removes infection as a cause,

the clean non-infected revision rates were slightly higher for antibiotic shunts. The cause is

unclear but one hypothesis is that the antibiotic catheters may convert an ‘infected’ shunt

revision into an apparently ‘clean’ shunt revision. This might occur because low virulent

pathogens are restricted to a biofilm in the valve (which is not impregnated) that does not

cause detectable changes in the CSF (such as increased white cell count) as there is no

ventriculitis and the bacteria are low in number or not able to grow in the presence of the

eluted antibiotics. However, changes in CSF composition and flow (such as debris or high

protein) may lead to blockage of the intricate valve mechanism. Our study was not powered

or designed to answer this question directly, but it will serve as a future important research

question. Nevertheless, from the patient perspective, whilst mechanical shunt revision still

requires surgery which may impact on their quality of life, the hospital admission is short,

prolonged antibiotics are not required and patients recover more quickly with fewer long-

term neurological sequelae when compared to shunt infection.7,8

18

Complications associated with shunt failures are expensive to manage.25-27 Economic

analyses suggest that the use of impregnated shunts that result in fewer complications, even

if more expensive to purchase, could be cost-effective or yield cost savings. 10,28,29 The cost-

effectiveness analysis within BASICS estimated that while antibiotic shunts are twice the

price of standard, there are expected to be cost-savings overall; although, based on the

primary economic outcome this may be at the expense of additional cases of shunt failures

(due to any cause) with silver and antibiotic compared to standard. The secondary economic

outcome based on the incremental cost per shunt infection averted is relevant as a reduced

infection rate is expected to be associated with reduced need of further surgery and

prolonged hospital care. Compared with standard, silver shunts were dominated, but

antibiotic shunts were dominant, saving £4,059 per 0·030 fewer infection-related failures;

equating to £135,753 per infection avoided. The cost-utility analysis was limited with respect

to missing data, and exclusion of participants who were at highest risk of shunt infections.

The strengths of this study are that: (i) infections were centrally classified blind to treatment

allocation thereby removing the risk of bias by the treating neurosurgeon; (ii) participant

retention was very high due to the nature of the intervention and the primary outcome

(patients with infected shunts are always re-admitted to hospital); (iii) patient withdrawal

was low (n=53, 3·3%) so it is unlikely events were missed; (iv) participants were recruited

across the whole of the UK and Republic of Ireland to encompass all ages and socio-

economic classes; (v) the study samples size was large; and (vi) the results have wide

generalizability because we did not mandate a specific surgical shunt insertion technique.

Some limitations of the trial should be noted. First it was not possible to blind the treating

neurosurgeon to the shunt type because the physical appearance of the shunts is distinctive.

19

Shunt type was blinded to the patient and not recorded in the patient records. The majority

of shunt revisions and removals for infection happen as emergencies and are managed by

the emergency neurosurgery team. Therefore, the likelihood of the same neurosurgeon who

inserted the shunt being involved in the decision to remove it was low given the work rotas

of neurosurgical staff. Furthermore, classification of shunt infection between treating

neurosurgeon and central assessment had high agreement (95·7%), suggesting that any

bias that the treating neurosurgeon may have had did not impact the study conclusion.

Second, ventriculoatrial and ventriculopleural shunts were excluded although we postulate

the results are translatable to patients undergoing these procedures. Finally, the return rate

for patient reported outcomes was low limiting the analysis of the impact of shunt infection

on patients, and the reliability of the cost utility analysis.

The BASICS study is the largest prospective randomised study for shunts in

hydrocephalus worldwide. The study collected blood and CSF samples from participants

that will be used for future research into biomarkers for infection and host response.

Data on hydrocephalus aetiology, surgical techniques, types of valves and technology

used will be analysed and used to will be analysed and used to develop

recommendations and healthcare policy for patients undergoing insertion of

ventriculoperitoneal shunts.

In conclusion, antibiotic shunts significantly reduce the infection rate and probability of

infection compared to standard shunts in all age groups, whereas silver shunts do not. The

routine use of these shunts would carry substantial costs savings. Antibiotic shunts should be

the first choice for patients with hydrocephalus undergoing insertion of their first

ventriculoperitoneal shunt.

20

Panel: Research in context

Evidence before this study

A systematic review comparing antibiotic against standard shunts identified one randomised

trial, one prospective cohort study and ten retrospective studies; none were adequately

powered to detect a difference in infection rates. There were no randomised trials of silver

versus standard shunts. Neurosurgeons were using antibiotic and silver shunts aiming to

reduce infection despite a lack of firm evidence to support this and at increased financial

cost.

Added value of this study

This is the largest randomised trial for ventriculoperitoneal shunts in hydrocephalus.

Antibiotic shunts significantly reduce the risk of infection compared to standard shunts in all

ages. Silver shunts have the same infection rate as standard shunts. From the perspective of

the NHS healthcare system antibiotic shunts save £135,753 per infection avoided.

Implications of the available evidence

From both the patient perspective and that of the treating neurosurgeon, the hospital and

the health service, every effort to reduce shunt infection should be made and health

technologies such as impreganted shunts with their potential to reduce such infections

deserve proper evaluation through appropriately planned and powered trials. Having

demonstrated a marked reduction in such infections, with all of the potentially catastrophic

and life changing health sequalae that result from each infection, the BASICS trial has

provided definitive evidence to support the adoption of antibiotic shunts in all patients

having their first ventriculoperitoneal shunt in the UK. The increased up-front cost of the

antibiotic shunt is offset by the added health economic benefit. The benefits and

implications both from an efficacy and health economic point of view are most pronounced

21

the younger the patient. The broader, global implications of these findings require

consideration of generalizability across different healthcare systems.

Contributors

Conor L Mallucci (Chief Investigator and Consultant Neurosurgeon) devised the study

question and developed the study protocol in collaboration with co-investigators. He

oversaw the delivery of the study, prepared study update reports, over saw clinical

aspects of the statistical analysis plan and clinical interpretation of the study data. He co-

led the preparation of the final report (drafting, reviewing and editing). He was

Chairperson of the Trial Management Committee and member of the Central Review

Panel. Joint first author.

Michael D Jenkinson (co-Chief Investigator and Consultant Neurosurgeon) devised the

study question and developed the funding application and study protocol in

collaboration with co-investigators. He was a member of the Trial Management

Committee. He contributed to clinical interpretation of the study data and co-led the

preparation of the final report (drafting, reviewing and editing). Joint first author.

Elizabeth J Conroy (Trial Statistician) contributed to protocol development and data

capture methods, wrote the statistical analysis plan, undertook the final statistical

analysis under the supervision of Carrol Gamble, prepared data for reports throughout

the study, prepared data tables and figures for final report, and co-led the preparation of

the final report. She was a member of the Trial Management Committee.

John C Hartley (Study microbiologist) contributed to protocol development, data

capture methods, central classification of infections, preparation and review of progress

and final reports. He was a member of the Trial Management Committee.

Michaela Brown (Senior Statistician) contributed to protocol development and data

capture methods, proposed statistical analysis methods and approved the statistical

22

analysis plan, oversaw trial monitoring activities and was a member of the Trial

Management Committee.

Tracy Moitt (Senior Trials Manager) contributed to protocol development, gave

guidance and support on all aspects of governance and study delivery and supported the

preparation of progress reports. She contributed to the final report (drafting and

reviewer) and was a member of the Trial Management Committee.

Joanne Dalton (Data Manager) supported the Central Review Panel in their assessment

and was a member of the Trial Management Committee.

Tom Kearns (Trial Co-ordinator) contributed to protocol development, all aspects of

governance and study delivery and preparation of progress reports. He contributed to

the final report (reviewer) and was a member of the Trial Management Committee.

Michael J Griffiths (Senior Lecturer in Paediatic Neurology), coordinated and

developed the sample collection sub-study, contributed to protocol development,

oversaw sample recruitment, collection and storage, contributed to the preparation of

the final report (reviewing, editing). He was a member of the Trial Management

Committee.

Giovanna Culeddu (Study Health Economist) contributed to protocol development and

data capture methods, undertook the economic analysis under the supervision of Dyfrig

Hughes, contributed to the final report (drafting) and was a member of the Trial

Management Committee.

Tom Solomon (Professor of Neurology), assisted with obtaining grant funding, was a

member of the Trial Management Committee, and reviewed the final report

Dyfrig Hughes (Senior Health Economist) led the economic evaluation, contributed to

protocol development and data capture methods, contributed to the writing of the

report (drafting, reviewing and editing) and was a member of the Trial Management

Committee.

23

Carrol Gamble (Statistical lead) led study design, developed the funding application,

study protocol and data capture methods in collaboration with co-investigators. CG led

blind review of the data and supervised the final analysis. She contributed to the

preparation of the final report (drafting, reviewing and editing) and was a member of

the Trial Management Committee.

Declaration of interests

MDJ receives grant funding from Vitaflo Ltd, has provided consultancy services and received

honoraria from Brainlab. TS is an advisor to the GSK Ebola Vaccine programme and chairs a

Siemens Diagnostics Clinical Advisory Board. All other co-authors have no competing

interests to declare.

Role of funding source

This study was funded by the National Institute for Health Research Health Technology

Assessment programme (NIHR-HTA) under grant agreement 10/104/30. The corresponding

author had full access to the data and final responsibility to for the decision to submit the

manuscript for publication.

Data sharing agreement

Individual participant data that underlie the results reported in this article, after

deidentification, will be made available. The study protocol, statistical analysis plan and

consent forms will also be made available. Data will be available beginning 9 months and

ending 3 years after publication. Data will be available to researchers whose proposed use

of the data is approved by the original study investigators. Proposals should be directed to

the corresponding authors and requestors will need to sign a data access agreement.

24

Disclaimer

The views expressed are those of the authors and not necessarily those of the NHS, the NIHR

or the Department of Health and Social Care.

25

References

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19. Department of Health and Social Care. NHS reference costs 2015 to 2016. https://www.gov.uk/government/publications/nhs-reference-costs-2015-to-2016 (accessed 10 March 2019.20. NHS England. NHS national tariff payment system 2016/17. https://www.gov.uk/government/publications/nhs-national-tariff-payment-system-201617 (accessed 10 March 2019.21. Joint Formulary Committee. British National Formulary (BNF). London: BMJ Group and Pharmaceutical Press; 2017.22. Govender ST, Nathoo N, van Dellen JR. Evaluation of an antibiotic-impregnated shunt system for the treatment of hydrocephalus. J Neurosurg 2003; 99(5): 831-9.23. Keong NC, Bulters DO, Richards HK, et al. The SILVER (Silver Impregnated Line Versus EVD Randomized trial): a double-blind, prospective, randomized, controlled trial of an intervention to reduce the rate of external ventricular drain infection. Neurosurgery 2012; 71(2): 394-403; discussion 03-4.24. Jamjoom AAB, Joannides AJ, Poon MT, et al. Prospective, multicentre study of external ventricular drainage-related infections in the UK and Ireland. J Neurol Neurosurg Psychiatry 2018; 89(2): 120-26.25. Attenello FJ, Garces-Ambrossi GL, Zaidi HA, Sciubba DM, Jallo GI. Hospital costs associated with shunt infections in patients receiving antibiotic-impregnated shunt catheters versus standard shunt catheters. Neurosurgery 2010; 66(2): 284-9; discussion 89.26. Farber SH, Parker SL, Adogwa O, Rigamonti D, McGirt MJ. Cost analysis of antibiotic-impregnated catheters in the treatment of hydrocephalus in adult patients. World Neurosurg 2010; 74(4-5): 528-31.27. Parker SL, McGirt MJ, Murphy JA, Megerian JT, Stout M, Engelhart L. Cost savings associated with antibiotic-impregnated shunt catheters in the treatment of adult and pediatric hydrocephalus. World Neurosurg 2015; 83(3): 382-6.28. Edwards NC, Engelhart L, Casamento EM, McGirt MJ. Cost-consequence analysis of antibiotic-impregnated shunts and external ventricular drains in hydrocephalus. J Neurosurg 2015; 122(1): 139-47.29. Root BK, Barrena BG, Mackenzie TA, Bauer DF. Antibiotic Impregnated External Ventricular Drains: Meta and Cost Analysis. World Neurosurg 2016; 86: 306-15.

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Tables

Table 1

Baseline patient characteristics and physical examination of the intention to treat population

Baseline Characteristic Standard shunt Antibiotic shunt Silver shunt Total

Patients randomised 536 538 531 1605

Age at randomisation (years)

N 536 538 531 1605

Med (LQ - UQ) 42·5 (0·8 – 69·7) 43·9(1·1 – 70·8) 41·1 (0·5 – 68·8) 42·5 (0·8 – 69·6)

(Min, Max) (0·0, 90·3) (0·0, 88·9) (0·0, 91·1) (0·0, 91·1)

Age category, n (%)

Paediatric 200 (37·3) 201 (37·4) 198 (37·3) 599 (37·3)

Adult (<65 years) 174 (32·5) 156 (29·0) 172 (32·4) 502 (31·3)

Adult (≥65 years) 162 (30·2) 181 (33·6) 161 (30·3) 504 (31·4)

Gender, n (%)

Female 246 (46·0) 260 (48·3) 282 (53·1) 788 (49·1)

Male 289 (54·0) 278 (51·7) 249 (46·9) 816 (50·9)

Missing 1 0 0 1

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Note: Med: Median; LQ: Lower Quartile; UQ: Upper Quartile; Min: Minimum; Max: Maximum

Table 2

Summary of revisions, and reasons for revision, of first shunt according to catheter type and assessor

Standard shunt Antibiotic shunt Silver shunt Total

N % N % N % N %

Summary of surgeries

Randomised 536 538 531 1605

Eligible for primary outcome (1) 533 99·4 535 99·8 526 99·4 1594 99·6

No shunt removal/revision 403 75·6 403 75·3 390 74·1 1196 75·0

Shunt removal/revision (for

any cause)

130 24·4 132 24·7 136 25·9 398 25·0

Reason for revision as classified by central review

Reason for revision

Revision for infection 32 6·0 12 2·2 31 5·9 75 4·7

Revision for other reason

(no infection)

98 18·4 120 22·4 105 20·0 323 20·3

29

Type of infection

Shunt CSF or peritoneal

infection

Definite – Culture positive 22 68·8 6 50·0 25 80·6 53 70·7

Probable – Culture uncertain 1 3·1 0 0·0 2 6·5 3 4·0

Probable – Culture negative 3 9·4 3 25·0 1 3·2 7 9·3

Possible – Culture uncertain 1 3·1 0 0·0 1 3·2 2 2·7

Clinically classified infection

(2)

1 3·1 0 0·0 0 0·0 1 1·3

Shunt deep incisional infection

Shunt deep incisional

infection

4 12·5 3 25·0 2 6·5 9 12·0

Reason for shunt revision as classified by treating neurosurgeon

Suspected infection 33 6·2 15 2·8 30 5·7 78 4·9

Revision for other reason

(no infection)

97 18·2 117 21·9 106 20·2 320 20·1

1 Randomised participants that did not receive a shunt (n=4) and had infection at time of insertion (n=7) were excluded from the

primary outcome set, see Figure 2.

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2 Where the committee was unable to classify an infection, an infection was identified as reported on the case report forms. There

was one case where the committee was unable to classify and this was clinically classified as an infection.

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Table 3: Hazard ratio estimates from multivariate regression modelling

Primary outcome

Time to removal of the first

shunt due to infection, as

assessed by central review (1)

Model estimate N events csHR (97·5% CI) P-value sHR (97·5% CI) P-value

Shunt Standard 32 - - - - - -

Antibiotic 12 0·38 (0·18, 0·80) <0·01 0·38 (0·18, 0·80) <0·01

Silver 31 0·99 (0·56, 1·74) 0·96 0·99 (0·56, 1·72) 0·95

Age group Paediatric 47 - - - - - -

Adult (<65 years) 23 0·55 (0·31, 0·97) 0·02 0·56 (0·32, 0·99) 0·02

Adult (≥65 years) 5 0·12 (0·04, 0·34) <0·01 0·12 (0·04, 0·35) <0·01

Secondary outcomes

Time to removal of the first

shunt due to suspected

infection, as assessed by

treating neurosurgeon (1)

Model estimate N events csHR (97·5% CI) P-value sHR (97·5% CI) P-value

Shunt Standard 33 - - - - - -

Antibiotic 15 0·45 (0·23, 0·91) 0·01 0·45 (0·23, 0·91) 0·01

Silver 30 0·93 (0·53, 1·64) 0·77 0·92 (0·53, 1·61) 0·74

Age group Paediatric 50 . . . . . .

Adult (<65 years) 23 0·51 (0·29, 0·91) <0·01 0·53 (0·30, 0·93) 0·01

32

Adult (≥65 years) 5 0·11 (0·04, 0·31) <0·01 0·12 (0·04, 0·33) <0·01

Time to removal/revision of the

first shunt for any cause (1)

Model estimate N events HR (97·5% CI) P-value

Shunt Standard 130 . . .

Antibiotic 132 1·01 (0·77, 1·33) 0·94

Silver 136 1·08 (0·82, 1·42) 0·54

Age group Paediatric 226 . . .

Adult (<65 years) 118 0·57 (0·44, 0·74) <0·01

Adult (≥65 years) 55 0·25 (0·18, 0·35) <0·01

Time to failure of second shunt

due to infection, following clean

revision (2)

Model estimate N events csHR (97·5% CI) P-value sHR (97.5% CI) P-value

Shunt Standard 9 - - - - - -

Antibiotic 6 0·55 (0·17, 1·81) 0·26 0·55 (0·17, 0·75) 0·25

Silver 5 0·47 (0·13, 1·63) 0·17 0·48 (0·14, 1·67) 0·19

Age group Paediatric 10 - - - - - -

Adult (<65 years) 9 1·64 (0·58, 4·61) 0·28 1·72 (0·62, 4·81) 0·24

Adult (≥65 years) 1 0·34 (0·03, 3·64) 0·14 0·37 (0·04, 3·91) 0·14

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csHR: Cause-specific hazard ratios from multivariate Cox model with infection as event of interest and both shunt and age group as covariates.

sHR: Sub-distribution hazard ratios from multivariate Fine-Gray model with infection as event of interest, revision not for infection as a competing risk, and

both shunt and age group as covariates.

HR: Hazard ratios from multivariate Cox model with revision/removal as event of interest and both shunt and age group as covariates.

Follow up time (in months) summary statistics: Median; LQ - UQ; Min to Max:

1Follow up time from first shunt 22; 10-24; 0 to 24.

2Follow up time from second shunt following clean revision: 9; 2-19; 0 to 24.

34